Follicular lymphoma (FL) is the most common form of non-Hodgkin's lymphoma, presenting as indolent follicular neoplasms that progress and transform to a high grade NHL-B. A major conundrum to understanding the biology of FL, has been the lack of proliferative capacity observed in freshly isolated FL cells from LN biopsies, either on flow cytometric analysis of lymphoma growth kinetics, or in in vitro studies measuring constitutive or mitogenic stimulation of purified FL cells. We have recently shown that members of the human B cell growth factor (BCGF) family of cytokines can stimulate in vitro cell growth in purified, freshly isolated FL cells, suggesting that paracrine cell growth may be operative in FL. Our studies will explore the role of these cytokines in regulating FL cell growth from various sites of disease involvement, as well as in relapsing or progressing stages of FL. Further studies will evaluate differences in growth potential between BM FL cells compared with FL cell populations from peripheral LNs, using BCGFs, and other putative B cell stimulatory cytokines. We hypothesize that transformation from FL to high grade NHL-B results from progressive immune deficiency, developing in FL patients with protracted clinical courses, primarily as a result of progressive replacement and undermining of normal T cell immunity. Studies to confirm and document this association will be performed. We will utilize our recently cloned cDNA for HMW-BCGF and another cDNA for a growth-related gene from a transformed (high grade) FL cell line to test our hypothesis that their expression is part of the transformation process to high grade NHL-B and autocrine growth. We will transfect these genes into FL cells stimulated with BCGFs in vitro to determine if these genes can influence the growth potential of FL cells in vitro, and when transplanted into immune deficient SCID mice. SCID mice will also be used to develop an in vivo murine model of FL, to evaluate growth potential of FL cells from different anatomic sites and stages of disease involvement, as well as to delineate genetic aspects of lymphoma progression and transformation to high grade NHL-B.